the role of hypoxia as a selective pressure for tp53 mutations

Conditions: Endometrial Cancer

Summary: the study aims to develop scans that tell the investigators about the oxygen content of tumours using magnetic resonance imaging (mri) and seeing whether regions of low oxygen content are related to mutations in cancer genes such as tp53. mri is a method of obtaining pictures of inside of the body that shows the appearance and structure of soft tissues. to get the information about the oxygen content of tumours, mri is carried out while breathing 100% oxygen. the variation of oxygen supply to different regions of the tumour will help the investigators to predict tumour behavior and tumour response to treatment.

cancer tissue harbours a multitude of genetic alterations, and it is well-established that when certain key alterations develop, they are powerful determinants of tumour behaviour (growth rate, potential to spread). one of the most sinister and well-recognized alterations is in a gene called tp53. another feature of tumours that results in resistance to treatment and poor outcome is a low oxygen level within tumour tissue. however, whether alterations in tp53 are driven by low oxygen levels is not established. endometrial cancer is a good model to study the relationship between low tumour oxygen levels and alterations in tp53 within tumour. firstly, it is a common gynaecological malignancy, (9,300 new cases annually in the uk) with two recognized types based on the appearance and behaviour of the tumour. in type i (endometrioid and mucinous carcinomas), alterations in tp53 are uncommon (15%), while in type ii (serous and clear cell carcinomas) they are common (88%). in-line with this, the survival of patients with type 2 cancer is worse. secondly, endometrial cancer is routinely assessed at diagnosis using magnetic resonance imaging. this non-invasive scanning technique can be manipulated to derive additional information about the oxygen status of the whole tumour and regions within it. finally, the primary management of endometrial cancer is surgical and involves hysterectomy. this means it is possible to obtain fresh tumour tissue at the time of surgery from regions that have been identified on imaging as having low vs.high levels of oxygen and to establish their tp53 status. in this study, therefore, the investigator will establish the regional oxygen distribution within endometrial cancers at diagnosis, and relate them to the alterations in tp53 from fresh tissue samples from selected regions using gene sequencing. understanding how highly deleterious mutations arise in cancer might provide new avenues for intervention and control.

Eligibility criteria:
inclusion criteria: 1. ≥18 years of age on the day of signing the informed consent. 2. histologically confirmed endometroid or serous endometrial cancer. 3. scheduled to have hysterectomy at the cancer centre 4. identifiable tumour mass on staging mri. 5. voluntarily agreed to participate by giving written informed consent. exclusion criteria: 1. life expectancy of \< 6 months. 2. ferromagnetic implants, contraindicating mri 3. claustrophobia so unable to tolerate mri 4. unable to lie flat 5. ascites sufficient to prevent patient being fitted in the scanner bore 6. histology unlikely to show variation in tp53 status, or heavily calcified disease. 7. radiotherapy to the abdomen or pelvis within 6 months of the screening visit. 8. unresolved bowel obstruction. 9. currently participating or has participated in a study with an investigational compound or device within 30 days of the start of treatment. 10. history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with patient's participation for the full duration of the study, or is not in the best interest of the patient to participate. 11. unlikely to comply with the requirements of the study.

Keywords: tp53 hypoxia endometriod and mucinous carcinomas serous and clear cell carcinomas magnetic resonance imaging, mri